Cancer treatment regimens are frequently challenged by multi-drug resistance as tumor cells adapt in response to drug treatment. Apoptosis, a type of programmed cell death, involves a series of biochemical events that lead to changes in cell morphology and death. The apoptotic process is executed in such a way as to safely dispose of cell fragments. By elucidating intracellular signal transduction pathways in cancer, however, it is possible for the structures and processes crucial for induction of cell death to be affected. Indeed, defective apoptosis processes have been implicated in numerous diseases. Excess apoptosis causes cell-loss diseases like ischemic damage. On the other hand, insufficient amounts of apoptosis results in uncontrolled cell proliferation such as cancer.
Changes occur with the progression of malignant gliomas, for example, that may be related to the activation of the PI-3K/AKT pathway (typically by PTEN loss or through growth factor activity such as EGFR). This survival pathway activates a number of adaptive changes that include among other things, a stimulus for angiogenesis, inhibitors to apoptosis, and metabolic shifts that promote activation of glycolysis, preferentially. Similarly, new targets of treatment for pancreatic cancer include targets of signal transduction pathways and molecules involved in angiogenesis, specifically, the ras oncogene signally pathway and inhibitors of the matrix metalloprotease (MMP) family.
Many cancers such as malignant gliomas and pancreatic cancer are intrinsically resistant to conventional therapies and represent significant therapeutic challenges. Malignant gliomas have an annual incidence of 6.4 cases per 100,000 (Central Brain Tumor Registry of the United States, 2002-2003) and are the most common subtype of primary brain tumors and the deadliest human cancers. In its most aggressive manifestation, glioblastoma multiforme (GBM), the median survival duration for patients ranges from 9 to 12 months, despite maximum treatment efforts. In fact, in approximately one-third of patients with GBM, tumors will continue to grow despite treatment with radiation and chemotherapy. Similarly, depending on the extent of the tumor at the time of diagnosis, the prognosis for pancreatic cancer is generally regarded as poor, with few victims still alive 5 years after diagnosis, and complete remission rare.
Further, in addition to the development of tumor resistance to treatments, another problem in treating malignant tumors is the toxicity of the treatment to normal tissues unaffected by disease. Often chemotherapy is targeted at killing rapidly-dividing cells regardless of whether those cells are normal or malignant. However, widespread cell death and the associated side effects of cancer treatments may not be necessary for tumor suppression if the growth control pathways of tumors can be disabled. For example, one approach is the use of therapy sensitization, i.e. using low dose of a standard treatment in combination with a drug that specifically targets crucial processes in the tumor cell, increasing the effects of the other drug.
Furthermore, combination therapies include vaccine based approaches in combination with the cytoreductive and immune-modulating elements of chemotherapy with the tumor cell cytotoxic specificity of immunotherapy. Combination therapies, however, are typically more difficult for both the patient and physician than therapies requiring only a single agent. Furthermore, certain tumors have an intrinsic resistance against radiotherapy and many chemotherapy modalities may be due to the differential and types of growth patterns that can represent various degrees of hypoxic regions within individual tumors. For example, gliomas can grow in predominately infiltrative fashion with little to no contrast enhancement seen on MRI scans versus more rapidly growing contrast enhancing mass lesions. Similarly, the early stages of pancreatic cancer can go undetected. Also, relative hypoxic areas can be seen both in the center of the rapidly growing tumor mass, which often has regions of necrosis associated with this, as well as some relatively hypoxic regions within the infiltrative component of the tumor as well. Accordingly, some of these relatively hypoxic regions may have cells, which are cycling at a slower rate and may therefore be resistant to chemotherapy agents.
Recently, certain proposed cancer therapies target the use of glycolytic inhibitors. This type of inhibitor is designed to benefit from the selectivity resulting when a cell switches from aerobic to anaerobic metabolism. Because of the growth of the tumor, cancer cells become removed from the blood (oxygen supply). Under hypoxia, the tumor cells up-regulate expression of both glucose transporters and glycolytic enzymes, in turn, favoring an increased uptake of the glucose analogs as compared to normal cells in an aerobic environment. Blocking glycolysis in a cell in the blood will not kill the cell because the cell survives by using oxygen to burn fat and protein in their mitochondria to produce energy (via energy-storing molecules such as ATP). By contrast, when glycolysis is blocked in cells in a hypoxic environment, the cell dies, because without oxygen, the cell is unable to produce energy via mitochondria) oxidation of fat and protein. Hence, while glycolytic inhibitors have shown promise to treat certain cancers, not all cancer cells exist in a hypoxic environment. Indeed, classic observations by Otto Warburg have demonstrated a preference of many tumors to preferentially utilize glycolysis for cellular energy production, even in the presence of adequate amounts of oxygen (termed oxidative glycolysis or the “Warburg effect”). This tumor adaptive response appears to hold true for malignant gliomas as well.
A need exists, therefore, for the treatment of cancers that show a resistance to chemotherapy, exhibit differential growth patterns or growth patterns that have various degrees of hypoxic regions within the tumor and/or have survival pathways which are a stimulus for angiogenesis or inhibit apoptosis.